Vias intracelulares da ação do Sildenafil no diabetes insipidus induzido pelo lítio / Sildenafil action in lithium-induced NDI: intracellular pathway

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

13/06/2012

RESUMO

Patients taking lithium to treat bipolar disorder often present polyuria and urinary concentrating defect. In addition, lithium-treated animals present lower cyclic adenosine monophosphate production in response to vasopressin. Sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, elevates intracellular cyclic guanosine monophosphate (cGMP) levels, leading to plasma membrane accumulation of aquaporin 2 (AQP2). Therefore, PDE inhibitors might induce AQP2 membrane insertion even without vasopressin receptor activation by activating a parallel cGMP-mediated signal transduction pathway. We investigated Sil pathways of action in rats with lithium-induced nephrogenic Diabetes Insipidus (NDI). Wistar rats received lithium (40 mmol/kg food) or not for 4 weeks (Li or control), some rats also receiving sildenafil (200 mg/kg food) in weeks 2-4, with or without lithium (Li+Sil orSil). Animals in Li group developed polyuria, decreased urinary osmolality and decreased expression of AQP2 in both the cytoplasmic fraction and the cell membrane and Sil reversed these changes. We also demonstrated that intracellular cGMP concentration was increased in papillary tubules treated with Sil. We found that PKA may be involved in the pathway of cGMP induced AQP2 phosphorylation. In addition, Sil treatment increases Creb phosphorylation. Creb phosphorylation, acts as AQP2 gene transcription factor. We also observed that Li decreases eNOS expression and treatment with Sil normalizes this alteration. We conclude that Sil treatment improves polyuria by increasing production and insertion of AQP2. Sil treatment may be beneficial to patients suffering from induced DIN Li

ASSUNTO(S)

aquaporin 2 aquaporina 2 cyclic amp response element-binding protein cyclic nucleotides diabetes insípido nefrogênico inibidores de fosfodiesterase lithium/adverse effects lítio/efeitos adversos nephrogenic diabetes insipidus nucleotídeos cíclicos phosphodiesterase inhibitors proteína da ligação ao elemento de resposta ao amp cíclico

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